Spasmolytics

ABSTRACT

Tertiary amines of formula 3 have a strong and prolonged spasmolytic effect, also after oral administration, on the smooth musculature of the tractus gastrointestinalis, the tractus urogenitalis and the bronchial system and have a low toxicity. 
     The compounds can be synthetized according to methods known per se and been formulated to pharmaceutical compositions.

The invention relates to spasmolytic compounds, to pharmaceuticalcompositions and to methods of preparing the compounds and compositions.

The compound of formula 1 is known as a spasmolytic from Dutch PatentSpecification 112,650, while the compound of formula 2 as a spasmolyticis described in the published Dutch Patent Application 6,611,111. Uponoral administration, however, both compounds have only a weak andshortlasting activity.

It is the object of the invention to provide compounds which exert aspecific, spasmolytic effect on the smooth musculature of the tractusgastrointestinalis, the tractus urogenitalis and the bronchial systemand show said effect also for a long time and to a considerable extentafter oral administration.

It has surprisingly been found that compounds of formula 3 and theirsalts formed with pharmaceutically acceptable acids distinguishconsiderably from the compounds of formulae 1 and 2 as regards theirproperties, in spite of the structure relationship.

In formula 3 the symbols have the following meanings: R₁ is an alkylgroup, an alkoxy group, an alkyl-thio group or a dialkylamino group,which substituents have maximally 2 carbon atoms, a hydroxy group, ahydrogen atom, a chlorine atom, or a fluorine atom; R₂ is a hydrogenatom or, if R₁ represents a hydrogen atom, moreover one of the remainingsubstituents summed up for R₁, while R₁ and R₂ both may represent analkoxy group having 1 or 2 C atoms or together a methylene dioxy orethylene dioxy group; R₃ is an alkyl group having 1 or 2 C atoms; R₄ isan alkyl group having 1 to 3 C atoms; R₅ is a branched or non-branchedalkylene group having 3 to 12 carbon atoms; X is an oxygen atom or anethylene dioxy group and R₆ is a branched or non-branched or cyclisedalkyl group having up to 8 C atoms. These compounds are new with theexception of the compound in which R₁ = OCH₃, R₂ = H, R₃ = CH.sub. 3, R₄= C₂ H₅, R₅ = (CH₂)₃, X = O and R₆ = C₂ H₅, which compound is describedin Rec. Trav. Chim., 80 431 (1961) as an intermediate product withoutthe statement of any pharmalogical property whatsoever.

The compounds have a strong spasmolytic activity on the smoothmusculature of the tractus gastro-intestinalis, the tractus urogenitalisand the bronchial system. Although said activity has a musculotropic anda neurotropic component, the compounds have no or substantially noperipheral parasympatolytic activities. The compounds exert theiractivity after parenteral and rectal administration and also after oraladministration. Notably the oral effect is considerably stronger andlonger lasting than that of the compounds of formulae 1 and 2. Thisholds good in particular for compounds in which R₁ = OCH₃ and R₂ = H.

A very strong activity was found in compounds in which R₅ has 3 to 5carbon atoms, in particular in compounds in which R₆ is a cyclopentylgroup or a cyclo-hexyl group. The compound in which R₁ = OCH₃, R₂ = H,R₃ = CH₃, R₄ = C₂ H₅, R₅ = (CH₂)₃ X = O and R₆ = cyclo C₆ H₁₁ and itssalts, however, are to be preferred.

On the basis of their properties, the compounds, after having beenbrought in a form suitable for administration, may be used for thetreatment of all kinds of spastic diseases or of hypermotility of thesmooth musculature of the tractus gastrointestinalis, the tractusurogenitalis and the bronchial system, for example, for ureteral colicand renal colic, abdominal colics, colitis, postcholocystectomicsyndrome, duodenal and ventricular ulcers, spastic colon, "irritablecolon" and the like.

The dosis in which the compounds are administered depends on the natureand the severity of the disease to be treated. As a rule, a daily oraldose of from 5 to 50 mg will be chosen for adults. For animals the oraldosage is about 0.1-20 mg per kg.

The compounds have a low toxicity. The LD₅₀ values for oraladministration are as a rule above 200 mg per kg.

The spasmolytic activity of the compounds of formula 3 was measuredinter alia in a test on starved guinea pigs of 500 to 700 gr. Theanimals were narcotised by intermuscular injection of 1.25 g/kg ofurethane. After canules had been inserted into the trache and the venajugularis, the abdomen was opened and an actively moving loop of theileum was selected and tied off. The animals were placed at 37° C in abath containing Tyrode's solution in such manner that the abdomen wasfully immersed. The tied-off part of the ileum was connected to a watermanometer.

By means of an injection syringe of 20 ml which was connected to thewater manometer, the base pressure was adjusted at a value at which nospontaneous contractions occurred. Contractions were produced by theintravenous administration of 2.5 γ carbachol every 7 minutes. Thecontractions were recorded on a kymograph. After a constant response tothe spasmogen had been obtained, a test compound was administeredintraduodenally. For that purpose, a thin rubber catheter was insertedorally and secured in the duodenum.

Three minutes after the administration of the test compound, carbacholwas injected. The administration of said spasmogen was repeated every 7minutes.

The contractions as a result of the spasmogen after the administrationof the test compound were expressed in percent of the contractionsobtained prior to the administration of the test compound. In thismanner both the strength and the duration of the activity weredetermined.

The new compounds of formula 3 and their salts can be obtained by meansof methods which are known for the synthesis of this type of compoundsand by means of methods analogous thereto.

In agreement herewith, the invention also relates to a method ofpreparing new tertiary amines, characterized in that compounds offormula 3, in which the symbols have the above-described meanings, andsalts thereof formed with pharmaceutically acceptable acids, but withthe exception of the compound of formula 3 in which R₁ = OCH₃, R₂ = H,R₃ = CH₃, R₄ = C₂ H₅, R₅ = (CH₂)₃, X = O and R₆ = C₂ H₅, are preparedaccording to methods which are known for the preparation of this type ofcompounds and according to methods analogous thereto.

For example, the compounds can be obtained by reacting a compound offormula 4 with a compound of formula 5. In these formulae Y₁ representseither the group ##STR1## in which case Y₂ means the group ##STR2## andY₃ the group R₄ or conversely, or Y₁ represents the group ##STR3## Y₂the group R₄ and Y₃ the group ##STR4## In formula 5, Hal is a halogenatom or a tosyloxy group, but preferably an iodine atom. The reaction ispreferably carried out in an inert solvent, for example, acetonitrile,petroleum ether, benzene, toluene, acetone, methyl ethyl ketone,methanol and ethanol. The reaction mixture may comprise an acid binder,for example, a tertiary amine such as triethylamine, pyridine andguinoline or an inorganic base, for example, potassium carbonate. Anexcess of amine of formula 4 may also serve as such. The reactiontemperature is between -20° and 200° C.

If desired, compounds of formula 3, in which X is an ethylene dioxygroup, can be hydrolysed to the corresponding ketones by means of acid.For said hydrolysis, dilute acids may be used, for example, sulphuricacid and hydrochloric acid, possibly mixed with an organic solvent, forexample, acetone. The reaction temperature as a rule is between roomtemperature and the boiling point of the mixture.

Compounds of formula 3 in which X is an oxygen atom may also be obtainedby oxidizing a compound of formula 6. Said reaction can be carried outwith potassium permanganate or sodium bichromate in, for example,acetone, methyl ethyl ketone, water or acetic acid.

The ketones of formula 3 can also be obtained by reacting a compound offormula 7, in which Z is a nitril group or a lower alkoxycarbonyl group,with a Grignard reagent of formula 8, in which Hal' is a chlorine atomor bromine atom. The reaction may be carried out in ethers, for example,diethyl ether, dioxane, tetrahydrofurane, at temperatures between -20° Cand the boiling point of the mixture.

According to another method, the ketones of formula 3 are obtained byreacting a compound of formula 9 with a compound of formula 10, in whichHal' is a chlorine atom or a bromine atom and R is a lower alkyl group,succeeded by saponification and decarboxylation of the formed acid with,for example, dilute acid at temperatures between room temperature andthe boiling point of the mixture. R'₅ is an alkylene group having 2 to11 C atoms.

Compounds of formula 3 can furthermore be prepared by reduction of acompound of formula 11 to prepare ketones of formula 3 succeeded by acidhydrolysis of the ketal group. The reduction is carried out with ahydride, for example LiAlH₄ in ethers, for example, diethyl ether,dioxane and tetrahydrofurane as a solvent. The reaction temperature as arule is between -10 and the boiling point of the mixture.

As examples of pharmaceutically acceptable acids with which theaminoketones according to the invention can form salts may be mentioned:hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid,p-toluenesulphonic acid, benzoic acid, acetic acid, propionic acid,tartaric acid, succinic acid, citric acid, fumaric acid, maleic acid.

The compounds can be brought in a form suitable for administration bymeans of methods known per se. The compounds may be mixed with ordissolved in solid or liquid carrier materials. The resulting mixturesor solutions can be processed to pharmaceutical dosage unit forms, forexample, capsules, tablets, coated tablets, pills and suppositories.

The invention will be described in greater detail with reference to theensuing specific examples. If not stated to the contrary in theexamples, the compounds were obtained as a high-boiling-point oil, theboiling point of which could not be established as a result ofdecomposition. Nor was it possible in that case to obtain acrystallising salt. The compounds were characterized by means of NMR-,IR- and elementary analysis.

EXAMPLES

1. 8-[n-ethyl-[1-methyl-2-(4-methoxyphenyl)]ethylamino]-octanone-3

A mixture of 9.2 g of N-ethyl-[1-methyl-2-(4-methoxyphenyl)]-ethylamine,4.85 g of triethylamine, 12 g of 8-bromooctanone-3 and 7 g of sodiumiodide was boiled under reflux for 40 hours while stirring in 100 ml ofmethyl ethyl ketone. After distilling off the solvent, the residue wastaken up in 300 ml of water. Extraction was then carried out with 2×200ml of diethyl ether. The ether extract was extracted with 2×200 ml of 2NHCl. The acid water phase was then rendered basic with concentratedammonia, after which the tertiary amine was extracted with 3×100 ml ofether. After drying on sodium sulphate the extract was evaporated todryness, the above-mentioned substance being obtained. Obtained in ananalogous manner were:

2. 9-[N-ethyl[1-methyl-2-(3-methoxyphenyl)]ethylamino]nonanone-6.

3.2-[4-[N-ethyl-[1-methyl-2-(4-methoxyphenyl)]ethylaminobutyl]-2-methyl-1,3-dioxolane

A mixture of 30.9 g ofN-ethyl-[1-methyl-2-(4-methoxyphenyl)]-ethylamine, 14.3 g of2-(4-chlorobutyl)-2-methyl-1,3-dioxolane and 12 g of sodium iodide in130 ml of methyl ethyl ketone was converted into the title compound inaccordance with example 1.

In a manner analogous to Example 3 were contained:

4.2-[3-[N-ethyl-[1-methyl-2-(4-methoxyphenyl)]ethylamino]propyl]-2-methyl-1,3-dioxolane.

5.2-[5-[N-ethyl-[1-methyl-2-(4-methoxyphenyl)]ethylamino]-pentyl]-2-methyl-1,3-dioxolane.

6.2-[5-[N-ethyl-[1-methyl-2-(4-methoxyphenyl)]ethylamino]-pentyl]-2-ethyl-1,3-dioxolane.

7.2-[3-[N-ethyl-[(1-methyl-2-(4-methoxyphenyl)]ethylamino]propyl]-2-t.propyl-1,3-dioxolane.

8.2-[3-[N-ethyl-[1-methyl-2-(4-methoxyphenyl)]ethylamino]propyl]-2-propyl-1,3-dioxolane.

9.2-[4-[N-ethyl-[1-methyl-2-(4-methoxyphenyl)]ethylamino]butyl]-2-propyl-1,3-dioxolane.

10.2-[3-[N-ethyl-[1-methyl-2-(4-methoxyphenyl)]ethylamino]-propyl]-2-butyl-1,3-dioxolane.

11.2-[3-[N-ethyl-[1-methyl-2-(4-methoxyphenyl)]ethylamino]-propyl]-2-pentyl-1,3-dioxolane.

12.2-[3-[N-ethyl-[1-methyl-2-(4-methoxyphenyl)]ethylamino]-propyl]-2-cyclohexyl-1,3-dioxolane.

13. 6-[N-ethyl-[1-methyl-2-(4-methoxyphenyl)]-ethylamino]hexanone-2.

12 g of the 1,3-dioxolane obtained according to Example 3 were heated atapproximately 90° C for 1 hour in 480 ml of acetone with 42 ml of 2Nsulphuric acid. After cooling, the solution was rendered basic withconcentrated ammonia (pH 10) and the acetone was evaporated. After theaddition of 200 ml of water to the residue, extraction was carried outwith 3×100 ml of ether. The ether extract was then extracted with 3×100ml of 2N HCl, after which the acid water layer was rendered alkalinewith concentrated ammonia (pH 10). The free precipitated as an oil wasthen taken up in ether (250 ml). After drying on sodium sulphate andevaporating the ether solution to dryness, the title compound wasobtained.

The following ketones were obtained in an analogous manner:

14. 5-[N-ethyl-[1-methyl-2-(4-methoxyphenyl)]-ethylamino]-pentanone-2.

15. 7-[N-ethyl-[1-methyl-2-(4-methoxyphenyl)]-ethylamino]heptanone-2.

16. 8-[N-ethyl-[1-methyl-2-(4-methoxyphenyl)]-ethylamino]octanone-3.

17.6-[N-ethyl-[1-methyl-2-(4-methoxyphenyl)]-ethylamino]-2-methylhexanone-3.

18. 7-[N-ethyl-[1-methyl-2-(4-methoxyphenyl)]-ethylamino]-heptanone-4.

19. 8-[N-ethyl-[1-methyl-2-(4-methoxyphenyl)]-ethylamino]-octanone-5.

20. 8-[N-ethyl-[1-methyl-2-(4-methoxyphenyl)]-ethylamino]-octanone-5.

21. 9[N-ethyl-[1-methyl-2-(4-methoxyphenyl)]-ethylamino]-nonanone-6.

22.3[N-ethyl-[1-methyl-2-(4-methoxyphenyl)]-ethylamino]-propylcyclohexylketone.

23. 8-[N-ethyl-[1-methyl-2-phenyl)-ethylamino]-octanone-5]

24.3-[N-ethyl-[1-methyl-2-(4-chlorophenyl)]ethylamino]-propylcyclohexylketone.HCl. Melting point 103°-106° C.

25.3-[n-ethyl-[1-methyl-2-(4-methoxyphenyl)]-ethylamino]-propylcyclohexylketone.

A solution of 65.6 g of cyclohexylbromide in 110 ml of diethylether wasconverted into the Grignard compound with 9.6 g of magnesium. Added tothe Grignard solution with stirring at 20° C within 20 minutes was asolution of 30.7 g ofγ-[N-ethyl-[1-methyl-2-(4-methoxyphenyl)]-ethylamino]-butyric acid ethylester in 160 ml of dry diethyl ether. The reaction was completed byrefluxing for 1 hour, after which the reaction product was decomposed at0° C with 200 ml of concentrated ammonium chloride solution. Afterseparation of the ether layer, the water layer was extracted with ether(3×200 ml). The resulting ether solution was washed with water (2×100ml), dried on sodium sulphate and evaporated to dryness. For the removalof a small quantity of starting product, the reaction product was thenboiled in a mixture of 800 ml of ethanol, 50 ml of water and 14 g ofpotassium carbonate for 24 hours. The solvent was then evaporated underreduced pressure and the residue was taken up in 250 ml of ether. Thesolution was extracted with 3×200 ml of 2N HCl. The aqueous solution wasextracted to pH 10 with ether (3×150 ml) after the addition ofconcentrated ammonia. The product obtained after drying on sodiumsulphate and evaporating to dryness was filtered over 500 g of silicagel to remove polar contaminations. The pure ketone was obtained byelution with methylene chloride to which acetone(10 to 25% by volume)had been added. The following ketones were obtained in an analogousmanner:

26.6-[N-ethyl-[1-methyl-2-(4-methoxyphenyl)]-ethylamino]-n-hexylcyclohexylketone.

27. 5-[N-ethyl-[1-methyl-2-(4-methoxyphenyl)]-ethylamino]-pentanone-2.

28.5-[N-ethyl[1-methyl-2-(4-methoxyphenyl)]-ethylamino]-3-methylpentanone-2.

29.3-[N-ethyl-[1-methyl-2-(4-methoxyphenyl)]-ethylamino]-propylcyclohexylketonehydrochloride.

1.75 ml of 3.4 N ethanolic hydrochloric acid were added to 2.1 g of thebase obtained according to Example 25 in 25 ml of ether, after which thesolvents were evaporated under reduced pressure. The resulting resinoussubstance was crystallized from 15 ml of isopropyl ether. Melting point92°-95° C. In a manner analogous to Examples 25 and 29 was obtained:

30.9-[N-ethyl-[1-methyl-2-(4-methoxyphenyl)]-ethylamino]-n-nonylcyclohexylketonehydrochloride. Melting point 69°-72° C.

31. 5-[n-ethyl-[1-methyl-2-(4-methoxyphenyl)]-ethylamino]-pentanone-2.

The title compound was obtained in the manner described in Example 25starting from 5.2 g ofγ-[N-ethyl-[1-methyl-2-(4-methoxyphenyl)]-ethylamino]-butyronitrile in30 ml of ether and a Grignard compound prepared from 4.25 g of methyliodide and 0.72 g of magnesium in 25 ml of ether.

32.3-[N-ethyl-[1-methyl-2-(4-methoxyphenyl)]-ethylamino]-propylcyclohexylketone.

A solution of 7.7 g of cyclohexoyl acetic acid ethyl ester in 40 ml ofdry benzene was added to a suspension of 0.68 g of sodium powder in 15ml of toluene. The mixture was stirred at 50° C for 30 minutes, afterwhich a solution of 7.6 g of2-[N-ethyl-[1-methyl-2-(4-methoxy-phenyl)]-ethylamino]-ethylchloride in7.5 ml of dry benzene was added dropwise with stirring in 10 minutes.After stirring for 5 hours at 55° C, the whole was cooled to roomtemperature after which it was washed with water (2×100 ml). The residueobtained after drying on sodium sulphate and evaporation to dryness washeated on a steam bath for 16 hours with 40 ml of 2N sulphuric acid.After cooling, the mixture was rendered basic by the addition ofpotassium carbonate (11.35 g). After the addition of another 100 ml ofwater, it was extracted with ether (3×100 ml). After drying on sodiumsulphate, the extract was evaporated to dryness and the residue waschromatographed over 270 g of silica gel in methylene chloride to which10% by volume of acetone had been added. In this manner the titlecompound was obtained. According to a NMR analysis, the substance wasidentical to the product obtained according to example 25. In a manneranalogous to Example 32 was obtained:

33. 7-[N-ethyl[1-methyl-2-(4-methoxyphenyl)]-ethylamino]-heptanone-4.

As examples of pharmaceutical compositions may be mentioned:

34. Capsules containing

25 mg of active substance

25 mg of lactose

0.5 mg of polyvinylpyrrolidon

4.0 mg of carboxymethylcellulose

1.0 mg of magnesium stearate.

35. Tablets of the composition stated in Example 36.

36. Suppositories containing

10 mg of active substance

1490 mg of oleum cocoa

37. Injection liquid containing

10 mg of active substance

15 mg of benzyl alcohol

pyrogen-free distolled water to 1 ml.

What is claimed is:
 1. Compounds of the formula ##STR5## in which R₁represents an alkyl group, an alkylthio group or a dialkylamino grouphaving up to 2 carbon atoms per substituent, a hydroxy group, a hydrogenatom, a chlorine atom or a fluorine atom, R₂ is a hydrogen atom or, ifR₁ represents a hydrogen atom, in addition one of the remaining meaningsof R₁, while R₁ and R₂ both may represent an alkoxy group having up to 2carbon atoms, R₃ is an alkyl group having up to 2 carbon atoms, R₄ is analkyl group having up to 3 carbon atoms, R₅ is a branched ornon-branched alkylene group having 3 to 12 carbon atoms, X is anethylene dioxy group, R₆ is a branched or non-branched or cyclised alkylgroup having up to 8 carbon atoms and R₅ together with R₆ contains atleast 6 carbon atoms and salts thereof formed with pharmaceuticallyacceptable acids. 2.2-[3-[N-ethyl-[1-methyl-2-(4-methoxyphenyl)]ethylamino]-propyl]-2-methyl-1,3-dioxolaneas a compound of claim
 1. 3.2-[4-[N-ethyl-[1-methyl-2-(4-methoxyphenyl)]-ethylamino]-butyl]-2-methyl-1,3-dioxolaneas a compound of claim
 1. 4.2-[5-[N-ethyl-[1-methyl-2-(4-methoxyphenyl)]-ethylamino]-pentyl]-2-methyl-1,3-dioxolaneas a compound of claim
 1. 5.2-[5-[N-ethyl-[1-methyl-2-(4-methoxyphenyl)]-ethylamino]-pentyl]-2-ethyl-1,3-dioxolaneas a compound of claim
 1. 6.2-[3-[N-ethyl-[1-methyl-2-(4-methoxyphenyl)]-ethylamino]-propyl]-2-i.propyl-1,3-dioxolaneas a compound of claim
 1. 7.2-[3-[N-ethyl-[1-methyl-2-(4-methoxyphenyl)]-ethylamino]-propyl]-2-propyl-1,3-dioxolaneas a compound of claim
 1. 8.2-[4-[N-ethyl-[1-methyl-2-(4-methoxyphenyl)]-ethylamino]-butyl]-2-propyl-1,3-dioxolaneas a compound of claim 1, 9.2-[3-[N-ethyl-[1-methyl-2-(4-methoxyphenyl)]-ethylamino]-propyl-2-butyl-1,3-dioxolaneas a compound of claim
 1. 10.2-[3-[N-ethyl[1-methyl-2-(4-methoxyphenyl)]-ethylamino]-propyl]-2-pentyl-1,3-dioxolaneas a compound of claim
 1. 11.2-[3-[N-ethyl-[1-methyl-2-(4-methoxyphenyl)]-ethylamino]-propyl]-2-cyclohexyl-1,3-dioxolaneas a compound of claim 1.